Aquaporins (AQPs), a major class of integral membrane proteins found throughout all domains of life, selectively transport water and/or aliphatic alcohols and ammonia across membranes. There are 13 AQPs in humans that exhibit tissue specific expression. Defects in aquaporin function have been linked to a disparate number of human ailments including kidney dysfunction, brain oedema and vision loss. Brain oedema itself is a significant contributor to mortality and morbidity associated with many common neurological disorders. Indeed, disruption of the electrochemical gradient across the cell membranes, generated through active transport, is very disruptive to cellular viability. Thus, understanding the molecular basis for how AQPs function is a key objective within the aquaporin community. The goal of the proposed studies is to understand how AQPs are able to transport water across cellular membranes at near diffusion rates while preserving this electrochemical membrane potential. Mutational studies of AQPZ, one of two aquaporins from Escherichia coli, will be used to address this question. I also propose to facilitate the discovery of inhibitors that are selective for a particular AQP that is key to the red blood cell form of Plasmodium falciparum. Targeting AQPs with therapeutics may become a valuable avenue for combating disease. [unreadable] [unreadable] [unreadable]